Dietary iron deficiency impairs work performance by causing anemia and a decline in the oxidative capacity of muscle. These handicaps require adaptations of energy metabolism to maintain body function, especially when energy demands are increased by exercise. This proposal deals with four aspects of energy metabolism in sedentary and active rats with iron deficiency. 1. Gluconeogenesis. Iron- deficient rats have an increased reliance on gluconeogenesis. We plan to determine whether this is primarily an intrinsic function of the liver or whether it can be attributed to exogenous factors such as substrate availability, hormone regulation, or both. 2. Altered Mitochondrial Sensitivity to a Respiratory Signal. We plan to pursue evidence that the decreased oxidative capacity of skeletal muscle mitochondria in iron-deficient rats is associated with a decreased sensitivity to a respiratory signal, i.e., that the ATP/ADP ratio must fall to a lower than normal level in order to evoke a given respiratory rate. This change would provide a basis for the observed stimulation of glycolysis in iron-deficient skeletal muscle. 3. Hormonal Response to Activity. We plan to determine the thresholds for the hormone and enzyme responses as a function of exercise duration and intensity. We hypothesize that iron deficiency exaggerates the catecholamine and corticoid responses to exercise and that this, in turn, provides a mechanism for the beneficial effect of a very light training regimen on endurance and lactate homeostasis. 4. Ionic Iron is required for the activity of certain key enzymes in energy metabolism. We plan to evaluate the possible role of ionic iron in the pathophysiology of iron deficiency by a group of experiments involving work performance, and metabolism in the intact animal, in isolated hepatocytes, and in broken cell systems. We anticipate that the results of the proposed experiments will help to provide a metabolic basis for some manifestations of iron deficiency and lead to a better understanding of certain metabolic adaptations to exercise that are difficult to recognize under conditions of normal nutrition.